Idiopathic generalized epilepsy (IGE) constitutes a variety of epileptic disorders in humans, the most common being juvenile myoclonic epilepsy (JME). There is strong evidence that JME can be caused by a faulty genetic variation in the human gene bromodomain-containing protein 2 (BRD2). For this reason, many studies on BRD2 homologues have been conducted to determine the function of this protein. Studies on human BRD2 have revealed that certain polymorphisms in non-coding regions near the promoter are associated with JME. Knock-out experiments in mice reveal that the Brd2 deficient mice are smaller, display embryonic lethality, have slower cell proliferation in mouse embryonic fibroblasts and display defects during neurogenesis. Furthermore, studies in zebrafish confirm that Brd2 has a role in the development of vertebrates.
Juvenile myoclonic epilepsy (JME) is a form of idiopathic generalized epilepsy (IGE). JME is characterized by monoclonic seizures, which consists of small jerks of the arms, shoulders and sometimes legs. It accounts for 26% of all IGEs and begins by late childhood or early adolescence1. Many forms of IGEs have been linked to a single genetic mutation that follows Mendelian Inheritance; however it appears that there is a more complex mechanism that causes JME2,3. Another insight on the causation of this disorder is that there are many genes associated with JME, in particular the EJM1 locus on chromosome 6, as shown by Greenberg and collegues by linkage analysis4. EJM1 was later found to include bromodomain-containing protein 2 (BRD2)1,3,5. BRD2 has been characterized as a transcriptional activator of proteins involved in the cell cycle6. This has generated an interest in determining the function of BRD2 in embryogenesis. Researchers studying orthologs of BRD2 have discovered a role in brain development7,8,9 and this knowledge might help contribute to the diagnosis and treatment of JME.
JME is most commonly characterized by myoclonic seizures; however some individuals who have this disorder may also experience tonic-clonic seizures (extensive jerks of all limbs) and absence seizures (where responsiveness and awareness is disabled for a few seconds). Individuals who have two or more of any of these 3 types of seizures may have JME. Other characteristics of JME is that seizures often occur in the morning and that occur more often in females than in males10. Individuals with this disorder will most likely continue to have seizures if not otherwise treated with divalproex sodium. In a study conducted on individuals under 19 with JME, researchers using magnetic resonance imaging found aberrations in the corpus callosum, frontal lobe, hippocampus and prefrontal area of the brain11. The researchers in this study concluded that minimal discrepancies are present during the formation of neural networking in the developing brain of patients with JME11.
The mode of JME causation is not completely known. However, it is established that JME arises by genetic inheritance, where a family history of epilepsy is common. Thus far, five genes have been associated with JME: GABRA1, CLCN2, GABRD, EFHC1 and BRD2. All five of these proteins, even though are not within the same family, have evidence that associates them to improper neural networking. Both GABRA1 and GABRD are GABA receptors that when mutated, as in some individuals with JME, are desensitized to GABA (an inhibitory neurotransmitter) leading to increased neuronal excitability12,13. CLCN2 is also linked to GABA: it codes for a chloride channel present in areas of the brain that is sensitive to GABA and leads to increased neuronal excitability14. EFHC1 mutations was found to cause reduced neuronal cell death during development of mouse embryos15, where apoptosis is a common event during development. The fact that EFHC1partakes in inducing...